A difficult problem posed by many undesired immune responses in the eye, including potentially autoimmune diseases, is how to specifically inhibit the undesirable response without compromising the rest of the immune system, or inducing harms side effects. Despite progress made with immunosuppressive agents such as cyclosporin, the problems of specificity and side effects are essentially unsolved, especially for long-term applications. A promising approach is based on the finding that introduction of antigen into the gastrointestinal tract, i.e. feeding, can result in generation of peripheral tolerance, termed 'oral tolerance', to the antigen that is fed. The attractive features of oral tolerance are many; the inhibition is antigen-specific (although bystander suppression may be observed locally), no undesirable side-effects on the immune system or other systems have been observed, and administration of tolerogen is simple. A potentially important feature is that characterization of the recipient's immune response to the antigen, i.e. the daunting task of mapping of epitopes in an outbred population, is unnecessary since whole antigen is effective. Despite the encouraging results of early clinical trials, the mechanisms of oral tolerance, and hence our ability to manipulate the phenomena to best effect, are still unclear. The proposal focuses on the regulatory cells which mediate low dose oral tolerance in EAU (experimental autoimmune uveoretinitis), a CD4+ T cell mediated inflammatory disease of the uvea and retina that can be induced by retinal photoreceptor cell autoantigens. The following 7 questions are asked: 1) are additional protective sites present in the remaining 24 untested peptides of bovine S-Ag? 2) Can separate protective and pathogenic sites be distinguished in the 13 mer peptide 345-357? (which is able to induce EAU or protect from EAU depending on conditions of administration) 3) What is the nature of the regulatory cell? 4) Does activation of the regulatory cells require linked recognition of suppressor and helper epitopes? 5) Is generation of the regulatory cell dependent on 'help' from CD4+ T cells? 6) Does suppression take place at the site of immunization (or its draining node), or in the target tissue? and 7) Can unlinked recognition be exploited therapeutically?